This invention relates to processes for making colored pharmaceutical compositions useful in humans and other animals. In particular, it relates to such compositions, useful for the treatment of gastrointestinal disorders, containing an aqueous suspension of a bismuth-containing active material onto which a dye has been adsorbed.
Liquid suspensions can be generally defined as two-phase systems, wherein a finely divided solid is dispersed in a liquid medium. Many such formulations are described in the pharmaceutical literature, incorporating a variety of materials as suspending agents. See, for example, M. Pernarowski, "Solutions, Emulsions, and Suspensions", Remington's Pharmaceutical Sciences, Chapter 83 (A. Osol, et al., ed., 15th edition 1975), and The Theory and Practice of Industrial Pharmacy (L. Lachman, et al., ed., 2d edition 1976). One such product is sold by The Procter & Gamble Company under the trademark "Pepto-Bismol", for the treatment of nausea, heartburn, diarrhea and other gastrointestinal disorders. This product comprises an aqueous suspension of bismuth subsalicylate (at a level of about 1.75%, by weight) with methylcellulose and magnesium aluminum silicate. The formulation exhibits a high degree of consumer acceptability, with a color and viscosity which is particularly preferred. Indeed, the pink color of Pepto-Bismol.RTM. is commercially recognized and distinctly associated with the product and its generic copies. This color can be defined according to the L-a-b reflectance colorimetry scale, as approximately (L,a,b)=( 56, 48, -1.8), as measured on a Colorgard System 05 Colorimeter, Model 2000. The product employs a mixture of dyes to obtain this pink color: FD & C Red No. 3 and FD & C Red No. 40.
Pepto-Bismol is manufactured in a process which generally comprises the steps of first making an aqueous solution of the suspension agents (magnesium aluminum silicate and methylcellulose), followed by addition of FD & C Red 3 dye. The pH of this mixture is typically about 9.6. The bismuth subsalicylate is then added, as an aqueous slurry, lowering the product pH to approximately 6.5. The product is mixed, and then salicylic acid, sodium salicylate, FD & C Red 40 dye, sodium saccharin and a flavorant are added. The product pH is then about 3.5. Finally, the product is homogenized and packaged.
In the manufacture of any colored composition, it is important to maintain uniformity and reproducibility of color. Such uniformity is particularly important in the manufacture of products such as Pepto-Bismol, which are commercially-associated with a particular color. Further, the color of the product should remain stable, and not significantly change under typical conditions of storage. Such stability includes resistence to color fading from exposure to ultra-violet (fluorescent) light. The processes used to manufacture such products should also be easily implemented on a commercial production scale, and should be appropriate for production of pharmaceutically-acceptable products. It has been found that in the manufacture of Pepto-Bismol certain processing steps must be employed in order to obtain a preferred, colored product. In particular, it has been discovered that methods for manufacturing such bismuth-containing compositions, utilizing a particular order of processing steps, yield products with more uniform, reproducible and stable color than processes known in the art. Such processes of this invention also yield other advantages in maintaining the physical and chemical stability of the composition and its components, and in being readily implemented on a commercial production scale.